2-amino-5-spiro substituted oxazolin-4-one compounds

ABSTRACT

A NOVEL SERIES OF 2-AMINO-5-SPIRO SUBSTITUTED OXAZOLIN4-ONES AND INTERMEDIATES FOR MAKING SAID COMPOUNDS, THESE COMPOUNDS ARE PREPARED BY FIRST CONVERTING THE APPROPRIATELY SUBSTITUTED CYCLOKETONE TO THE CORRESPONDING CYCLOCYANOHYDRIN; CONVERTING THIS COMPOUND TO THE CORRESPONDING HYDROXY ACID; ESTERIFYING THE HYDROXY ACID, AND FINALLY CYCLIZING THE HYDROESTER TO FORM THE 2-AMINO5-SPIRO SUBSTITUTED OXAZOLIN-4-ONE. THESE COMPOUNDS EXHIBIT CENTRAL NERVOUS SYSTEM ACTIVITY AND ARE ACTIVE AS EITHER STIMULANTS OR DEPRESSANTS, AND SOME ARE USEFUL AS PERFORMANCE ENHANCERS.

United States Patent O 3,720,681 Z-AMINO-S-SPIRO SUBSTITUTED OXAZOLIN- 4-ONE COMPOUNDS Michael Raymond Harnden, Horsham, England, assignor to Abbott Laboratories, North Chicago, Ill.

No Drawing. Continuation-in-part of application Ser. No. 27,120, Apr. 9, 1970, which is a continuation-in-part of application Ser. No. 689,356, Dec. 11, 1967, both now abandoned. This application Aug. 10, 1971, Ser.

Int. Cl. C07d 85/40 US. Cl. 260293.66 4 Claims ABSTRACT OF THE DISCLOSURE CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of co-pending application Ser. No. 27,120, filed Apr. 9, 1970, now abandoned, which was a continuation-in-part of application Ser. No. 689,356, filed Dec. 11, 1967, now abandoned.

DETAILED DESCRIPTION OF THE INVENTION This invention is directed to a new series of chemical compounds consisting of Z-amino-S-spiro substituted oxazolin 4 ones. More specifically, this series of compounds includes those compounds having alicyclic spiro substituents at the -position of the oxazole ring as well as compounds having heterocyclic spiro substituents at the 5-position. All of the compounds of this invention exhibit central nervous system activity. Some of the compounds are CNS depressants. Others are stimulants.

The compounds of this invention are represented by structural Formula I:

wherein Z is a member selected from the group consisting of C to C cycloalkyl, lower alkyl-substituted C to C cycloalkyl, piperidine, lower alkyl-substituted piperidine and phenloweralkyl substituted piperidine.

The term lower alkyl as used herein refers to C -C straight, branched and cycloalkyl including methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, iso-butyl, t-butyl and cyclobutyl.

The stimulants of this invention are compounds of Formula II:

o Z F1TNHZ wherein Z is 3,5 dimethylcyclohexyl, 3,3,5 trimethylcyclohexyl, or 4-(N-methylpiperidine). The stimulants of Formula II are administered to animal in dosages'of' from 0.1 to 50 mg./kg. of body weight daily, preferably in divided doses.

The central nervous system depressants are represented by Formula III:

wherein Z is Q, to C cycloalkyl, 4-methylc'yclohexyl, 3,4,5 trimethylcyclohexyl, piperidine, 3,4,5 trimethylpiperidine, N-isopropyl-piperidine, or N-(2 phenethyl) piperidine. The compounds are administered to animals in need of tranquilization or sedation in dosages of from 20 to 500 mg./kg. daily, preferably in divided doses.

These compounds are prepared by first reacting an appropriately substituted cycloketone with a cyanide salt of an alkali metal to form the corresponding cyclocyanohydrin. This compound is then converted to the hydroxy acid by reaction with a strong acid, such as concentrated hydrochloric acid. The hydroxy acid derivative is then esterified by reaction with the appropriate alcohol to form an alkyl ester. This compound is then reacted with guanidine hydrochloride to form the spiro derivative.

The reactions leading to the intermediate compounds are standard reactions well known in the art, as are the intermediate compounds formed by those reactions. Thus, the cycloketones, cyclocyanohydrins, hydroxy acids and hydroxyesters are structurally familiar compounds. The S-spiro substituted derivatives are prepared by reacting the hydroxyester derivatives with guanidine in a suitable alcoholic solvent, such as methanol, ethanol, propanol and the like.

In order to better illustrate the invention disclosed herein, reference is made to the following examples which are presented to illustrate a few specific embodiments of this invention and not to limit same thereby.

EXAMPLE 1 1-hydroxy-3,S-dimethyl-cyclohexane carboxylic acid ethyl ester Part I: Cyanohydrin derivative.-A solution of 106.8 grams of sodium bisulphite in ml. of water is added dropwise with stirring over 30 minutes to a stirred mixture of 100 grams of 3,S-dimethylcyclohexanone, 67.0 grams of potassium cyanide and ml. of water. The reaction mixture is kept below 40 C. by means of a cold water bath. The reaction mixture is stirred for an additional 2 hours, the organic layer separated and the aqueous layer extracted with 250 ml. of ether three times. The combined organic layer and ether solutions are dried over magnesium sulfate and concentrated at reduced pressure to yield 40.3 grams of 1-hydroxy-3,S-dimethyl-cyclohexanecarbonitrile.

Part II: Hydroxy acid.-This product is then refluxed with stirring, with 300 ml. concentrated hydrochloric acid for 3 hours. The reaction mixture is concentrated at reduced pressure and the residue taken up in 250 ml. of chloroform and filtered to remove ammonium chloride. The filtrate is dried over magnesium sulfate and concentrated at reduced pressure. A syrup is obtained which upon trituration with 500 m1. of petroleum spirit and refrigeration at 50 overnight yields the crude hydroxy acid as white crystals. The crystals are filtered, dried and recrystallized from petroleum spirit to yield 9.50 grams of the pure 1-hydroxy-3,4-dimethylcyclohexane carboxylic acid.

Part III: Hydroxy ester.-The hydroxy acid is heated under reflux with 100 ml. of ethanol and 0.05 gram of p-toluene sulphonic acid for 8 hours. The solution is concentrated at reduced pressure, the residue dissolved in 100 ml. of ether and washed with 20 ml. of 10% so dium carbonate and 20 ml. water. The ether solution is dried over magnesium sulfate and concentrated at reduced pressure to yield 9.43 grams of the pure l-hydroxy- 3,5-dimethylcyclohexane carboxylic acid ethyl ester.

Following the procedure of Parts I, II and III in Example 1 above, various other hydroxy acids and their corresponding alkyl esters may be prepared. Table I below lists a representative series of the hydroxy acids prepared and their accompanying physical characteristics; while Table 11 below lists esters prepared from the corresponding acids prepared according to the description in 5 Part III of Example 1.

TABLE I Analysis, percent LR. absorption Percent Cale. Found OH C=O yield Emplrlcal-- M.P. in cmcm.- from Ex. Compound formula C H C H C. stretch. stretch. kctone 2 COOH 051130: 51.7 6.9 61.8 7.0 63-5 3,500(b) 1,700 18.7

3...;7. CDHIQOI 62.8 9.4 62.8 9.4 84-6 3,630(b) 1,700 24.1

COOH

44 H: CsHuOa 60.8 8.9 60.8 8.8 67-86 3.630(b) 1,700 34.8

HO COOH H0 COOH 6-.:.: CH; CmHrsOl 64.6 0.7 64.7 0.5 134-6 3.530(b) 1,700 33.3

HO COOH 7..7-2. CH1 CH3 611E190 66.0 10.1 00.2 10.0 126.9 3,530 1,700 33.1

CQ CH H0 COOH 8..;.;. OH C Hn0; 66.2 9.2 66.6 9.0 124-150 3,540(b') 1,700 23.6

COOH

10...: OH Cm nOa 64.6 9.7 64.4 9.7 131-3 3,620(b) 1,696 10.5

COOH OH;

1 Isomers.

6 Other hydroxy acids which may besynthesized include TABLE H HYDROXY ESTERS Cntinued l-hydroxycyclopentane carboxylic acid, l-hydroxycyclohexane carboxylic acid and l-hydroxycycloheptane car- Example Compound fiig g gg boxyhc acid, among others.

20 CH3 CH3 58.4 TABLE IL-HYDROXY ESTERS Percent yield CH: CH: Example Compound from acid I I HO/\COQC:H5

P00092111 0H 63,5 0H

12 7&3 2 5 22 OH 63.5 HO 0000211 COOCH 000C111, HOACOOCZHB CH;-

JJH;

The spiro compounds are prepared from the corresponding hydroxyesters prepared according to Example no 000093 1. Example 24 below describes the conversion of l- 15 54.9 hydroxy-3,5-dimethyl cyclohexane carboxylic acid ethyl ester of Example 1 to the spiro derivative.

EXAMPLE 24 110 0000111 2-amino-7,9-dimethyl-1-oxa-3-aza-spiro[4,51dec- I 2-en-4-one 16 0H; 49.3 CH3 HO 000055 17 57 4 A mixture of 9.43 grams of 1-hydroxy-3,5-dimethylc11, cyclohexane carboxylic acid ethyl ester with 4.38 grams of guanidine hydrochloride and 2.59 grams of potassium hydroxide pellets in 52 ml. of ethanol is refluxed for :1 v hour. The solution is cooled, diluted with 172 ml. of

H0 COOCIHfi water and brought to pH 7 with glacial acetic acid re- 18 85 4 sulting in a white precipitate being formed. After refrig- CH; CH; eration at 5 C. for 3 hours, the crystals are filtered, washed with water and ether, and dried yielding 3.20 grams of 2-amino-7,9-dimethyl-1-oxa-3-aza-spiro [4,S]dec- A 2-en-4-one, having a melting point of 276-81 C. H0 000C111 Elemental analysis.-Calcd. for C H N O (percent): 55 C, 61.2; H, 8.2; N, 14.3. Found (percent): C, 61.2; H, 19 8.3; N, 14.3.

Following the procedure of Example 24, other hydroxy esters, such as those described in Table II, may similarly be converted to the corresponding spiro derivatives. Table III below lists a representative series of such spiro HO derivatives prepared from the hydroxy esters listed in Table II and their accompanying physical characteristics.

TABLE III Analysis, percent LR. absorp- Percent Cale. Found M.P. tlon bands yield from Empirical in in 1,6001,800 hydroxy Ex. Compound formula C H N C H N O 0.111." region ester 25 COHEN-20: 51.4 6.8 20.0 51.5 5.8 20.0 1ss-93 1,660, 1,740 15.0

qirm.

The foregoing examples describe the various alicyclic spiro derivatives which form a part of this invention. The heterocyclic spiro substituents are prepared in a similar manner to that previously described herein, but for a clear understanding of this invention, the following examples are presented to further describe this novel series of compounds.

EXAMPLE 37 1-methyl-4-hydroxy-4-ca1'boethoxy piperidine 10 yielding 26.3 grams of 1-methyl-4-piperidone cyanohydrin.

The cyanohydrin is refluxed with stirring, with ml. concentrated hydrochloric acid for 3 hours. The solution is then concentrated at reduced pressure and the residue taken up in boiling alcohol, filtered hot, and the filtrate concentrated at reduced pressure to a white solid yielding 35.9 grams of 1-methyl-4-hydroxy-4-carboxy-piperidine hydrochloride.

The hydroxy acid hydrochloride is heated under reflux with 300 ml. of ethanol and 0.15 gram of p-toluene sulphonic acid for 16 hours. The solution is concentrated at reduced pressure and the residue treated with 200 ml. of 10% sodium carbonate solution, then extracted with 250 ml. of chloroform three times. The chloroform solution is washed with 100 ml. water, dried over magnesium sulfate and concentrated at reduced pressure. The clear liquid obtained is distilled and on cooling, solidifies to a white crystalline material yielding 16.5 grams of l-methyl- 4-hydroxy-4- carboethoxy piperidine having a boiling point of 93 95 at 1.2 mm. of pressure.

Elemental analysis.Calcd. for C H NO (percent): C, 57.7; H, 9.2; N, 7.5. Found (percent): C, 57.5; H, 9.2; N, 7.6.

In Table IV below are listed a representative number of other such hydroxy acid esters prepared in accordance with the procedure of Example 37, and their characteristic physical properties.

TABLE IV Analysis, percent; LR. absorption chloroform sol. Percent Cale. Found yield Empriieal --OH 0:0 from Ex. Compound formula C N C H N B.P.,G. stretch. stretch. ketone 38....- CIBH23N03 69.3 8.4 5.1 69.4 8.5 5.3 -4 at0.8mm 3,520 1,720 58.3

CH2|CH1 39 @011 CysHztNOa 68.4 8.0 5.3 68.7 8.1 5.3 1424i at 0.2mm 3,510 1,710 66.4

a l N HO CQzCzHs 40... $Ha CuHmNOs 61.4 9.8 6.5 61.4 10.1 6.6 111-5 at 4.0 mm.-. 3,575 1,720 62.1

N our-Q0111 41....: (J-1H5 CMHWNO: 59.7 9.5 7.0 59.6 9.5 6.9 77-80at0.5mm 3,510 1,710 51.7

Q HO 00202115 42...; (CH3): CnHmN O: 61.4 9.8 6.5 61.5 9.8 6.4 37-1038t 1.0 mm---. 3,515 1,710 30.2

compound.

EXAMPLE 43 Z-amiuo-8-methyl-3,8-diaza-spiro[4,5] dec-Z-en-one C Hz-N TNHI L A solution consisting of 43.5 grams of sodium methoxide in 1320 ml. of ethanol is added to a solution containing 78.0 grams of guanidine hydrochloride in 330 ml. of ethanol and the mixture stirred thoroughly. Sodium chloride precipitates out of solution and is removed by filtration. A solution of 150.3 grams of 1-methyl-4-hy- 12 droxy-4-carboethoxy-piperidine in 375 ml. of ethanol is then added to the filtrate and the resulting solution is refluxed with stirring for 1 hour. One liter of ethanol is removed by distillation at reduced pressure and the remaining solution cooled. On cooling a crystalline precipitate forms which is filtered and dried. The filtrate is then completely evaporated at reduced pressure and the residue obtained taken up in 100 ml. of fresh ethanol, cooled and additional precipitate is obtained. This procedure is repeated twice more until a total of 74.3 grams of crude product is obtained. The crude product is recrystallized from ethanol, filtered and dried, yielding 56.3 grams of 2-amino-8-methyl-3,8-diaza-spiro[4,5]dec-2-en-4-one having a melting point of 257-261 C.

Elemental analysis.Calc. for C H N 0 (percent): C, 52.4; H, 7.2; N, 22.9. Found (percent: C, 52.2; H, 7.3; N, 23.0.

The procedure of Example 43 may be followed to prepare other heterocyclic spiro compounds. In Table V below is listed those spiro substituents prepared from the corresponding hydroxy esters according to the procedure of Example 43 including the identifying physical characteristics of each.

TABLEV Analysis, percent LR. absorption Percent Cale. Found bands in 1,600- yield Empirical MP. 1,800 em: from Ex; Compound formula 0 H N C H N inC. region ester 44 CzHnNaOa 49.7 6.6 24.8 49.8 6.6 24.8 313-7 1,625.1,710 32.4

T O--N 45-. CH CliHlONlOi 65.9 7.0 15.4 65.6 7.1 15.6 253-8 1,660,],725 47.7

JlHr-N I NH: O -N 46...::: O CnHnNzO: 64.8 6.6 16.2 64.7 6.4 16.0 225-9 1,660,1,735 50.3

on.- Tim,

47...:::: CH; CWHHNOI 56.8 8.1 19.9 57.0 8.3 19.8 293-8 1,650,1,725 4.5

CHr-N O on Tum 48...:2: CoHiuNuO: 54.8 7.7 21.3 54.7 7.7 21.5 246- 1,680,1,730 37.1

Gang-N NH: 0- L 49...::: (CHI): CmHuNaOz 56.8 8.1 10.9 56.9 8.2 20.1 237-44 1,640,1,720 35.5

13 The foregoing Z-aminO-S-substituted spiro oxazolin-4- one compounds exhibit central nervous system activity; more specifically, most of these novel compounds are central nervous sysem depressants. A few of the com- EFFECT OF 2-AMINO-S-METHYL-l-OXA-3,8-DIAZASPIRO [4,5] DEG-Z-EN-4-ONE.INTRAPERITONEAL ADMINISTRATION pounds disclosed herein appear to exhibit stimulant ac- 5 Mean em em 6 e 111 tivity, rather than depressant actlvity. D S c Test compound When these compounds are administered to a group of (10 rug/kg.) mm test mice in dosages ranging up to 500 nulligrams per kilogram of body weight, the mice exhibit a general de- 29 85:0 3 90 oio 0 crease in activity being withdrawn and lethar ic. Table VI 10 29.5i0.5 29. 33:0:8 g 13 85:1 7 26 0:1:2 4 below details the activity of the various spec es of this 0 1 221E316 series along with the dosages utilized expressed in mg./ kg. g:%- g of body weight and the lethal dosage at which 50% of the 6:5:|:1: 6 18: 05:2: 3 animals expire (LD for each of the compounds. Unless 15 ggig-g otherwise indicated, the dosage and the LD Were ad- 1 s. 0:l:1.2 13.925117 mini tered by intraperitoneal injection. It is to be under- Retennontml stood, of course, that the particular route of administral1 hour aiterlast q s t on trial. tion is not critical to the manifestation of biological eifects.

TABLE VI Dosein LD 0 in Compound Activity mg./kg. mgJkg.

6-amino-5-oxa-7-azaspiro 3,4 oct-fi-en-S-one Depressant 200 500 2-amino-1-oxa-3-azaspiro 4,4 non-2en-4-one..- .do 500 1, 000 2-amino-1-oxa-3-azaspiro 4,5 dec-2-en-4- 200 1, 000 2-amino-l-oxa-3-azaspiro 4,6 undec-2en4-0ne 500 1, 000 2-amino-1oxa-3-azaspiro 4,7 dodec-2en-4- do 500 1, 000 2-amino-8-methyl-1-oxa--azaspiro[4,51dec-2-en-4- 500 1, 000 2-amino-7-methyl-1-oXa-3-az aspiro[4,5]dec-2-en-4-one 7 do 200 -750 2-amino-7,9-dimethyl-l-oxa-B-azaspiro[4,5]dec-2-en-4-one. Stimulant" 1 -300 2-amino-7,8,B-trimethyl-l-oxa-IS-azasprro[4,5]dee ?ren-4-one 200 1, 000 2-amino-7,7,9-trimethy1-1-oxa-3-azaspiro[4,5]dec-2-en-4-one 0. 1 750 2-amin0spir0[norbornane-2,5[2]oxaz olin]-4-one 500 1, 000 2-amino-octahydrospiro[naphthalene-20H),5-[2]oxazo11n] 4-on 5C0 1,000 2-amino-1-oxa-5,8-diazaspiro[4,51dee-2en-4-one 1,000 Z-amino-S-methyl-l-oxa-3,8-diazaspiro[4,5]dec-2-en-4-one 10 1, 000 2-amino8-benzy1-1-oxa-3,8-diazaspiro[4,5]dec-2-en-4-0ne 200 1, 000 2-amino-7,8,9-trimethy1-1-oxa-3 ,8-diazaspiro [4,5]-2-en-4-one 20 500 2-amino-8-isopropy1-1-oxa-3,8-d1azasprior-[4,5}dec-2-en-4-one 100 1, 000 Z-amino-8-phenethyl-1-oxa-3,8-diaZaspiro-[4,5 dec-2en-4-one ..do 200 1, 000

In addition to the foregoing activity, the administration of some of these novel compounds to warm-blooded animals results in an increased rate of learning by the animal coupled with a prolonged period of retention of the learned behavior.

The behavioral effects resulting from the administration of these compounds to rats were evaluated on a modified Cook-Weidley apparatus (L. Cook and E. Weidley, Ann. NY. Acad. Sci., 66, 740, 1957). The apparatus consists of a chamber with a grid flooring and an escape platform outside the chamber. The electric shock to the grid floor was controlled by a rheostat mechanism and scrambler. Rats were divided into 2 groups for each test trial. One group was administered saline as the control and the other group the test compound about /2 hour prior to electroconvulsive shock. It is known that electroconvlusive shock induces a state of proactive amnesia or an impaired learning rate (Deutsch, I. A., 1962, Ann. Rev. PsychoL, 24, 259). Then, 15 minutes after electroconvlusive shock, the rats were given 10 acquisition trials on the jump out test to measure learning rates. Each acquisition trial consisted of 15 seconds in the chamber without any stimulation followed by 10 seconds of buzzer stimulation and culminated by 5 seconds of buzzer-pluh-shock stimulation. The time from entrance into the apparatus until the rat jumps out is recorded as the escape time. Retention of the learned behavioral pattern was tested by repeating the test one hour after the last acquisition trial. The test sequence for each trial was terminated upon. successful completion of the task, e.g., jumping out of the chamber.

EFFECT OF 2-AMINO-7,7,9-TRIMETHYL-l-OXA-S-AZASPIRO [4,5] DEC-2-EN-4-ONE.INTRAPERITONEAL ADMINISTRATION Mean escape time (sec) Test compound 1 1 hour after last acquisition trial.

EFFECT OF 2-AMINO-7,9-DIMETHYL-1-OXA-3- AZASPIRO[4,5]DEO-2-EN-4-ONE.O RAL ADMINISTRATION Mean Escape Time (See) Test compound (20 mgJkg.) Contlo H Mb) s spwm r ps p New 1 1 hour after last acquisition trial.

wherein Z is 3,5-dimethylcyclohexyl, 3,3,5-trimethylcyclo- 15 16 I claim: 4. A compound in accordance with claim 1, said com- 1. A compound of the formula pound being 2-amino-8-methy1-1-oxa-3,8-diazaspiro [4,5]

0 dec-2-en-4-one. z 1%NH; References Cited 0 4 L 5 Harnden et al., J. Med. Chem. 1969, 12, 919-21.

Harnden et al., J. Med. Chem. 1970, 13 (2), 305-8.

hexyl, or 4 (N methylpiperidine) HENRY R. IRES, Primary Examiner pound being 2-amino-7, 9-dimethy1-1-oxa-3-azaspiro[4,5]

2. A compound in accordance with claim 1, said com- 10 G. T. TODD, Assistant Examiner dec-2-en-4-one.

US. Cl. X.R. 3. A compound in accordance with claim 1, said com- 2 pound being 2 amino 7,7,9-trimethyl-1-oxa-3-azaspiro 22 33 468 468 468 514 514 424 [4.5]dec-2-en-4-one. 

